This is a competing renewal for a mid-career investigator award application to support the efforts of Dr. Kathleen T. Brady, M.D., Ph.D. in conducting and mentoring patient-oriented drug abuse research. Dr. Brady has been continuously federally funded to conduct patient-oriented research with substance abusing individuals since completing her psychiatric residency training in 1989. Her particular areas of interest are in psychiatric comorbidity with substance use disorders and the pharmacotherapy of substance use disorders. In the period that has been supported by the initial application (1999-present), Dr. Brady has submitted a successful application to become a center in the NIDA Clinical Trials Network, and a successful center application to begin a specialized center for translational work on sex and gender factors affecting substance use disorders. She is also the site PI on a study of the genetics of cocaine dependence, and the PI for a core research component of two different MUSC research Centers (Alcohol Research Center and the Women's Research Center). These projects are focused on stress reactivity and relapse. In addition, during this funding period, she has served as a co-investigator for a number of studies involving pharmacotherapeutic interventions in individuals with substance use and co-morbid psychiatric disorders. Dr. Brady has a strong track record in mentoring in clinical research. In the period supported by the initial application, she has served as a primary or secondary mentor to five K-awardees and four post-doctoral fellows. She is currently the Director of the Addiction Psychiatry Fellowship Program and the Co-Director of a NIDA-funded post-doctoral research training program. She has recently been appointed as the Associate Director of the MUSC GCRC. The focus of her GCRC work will be to improve training opportunities and activities. Her long-term career goals are to continue work in patient-oriented substance abuse research in new directions that build on existing studies. During the period to be covered by this renewal, Dr. Brady plans to expand her exploration of the stress-relapse connections. She will continue to collaborate with basic science researchers in translational projects as well as initiate studies of pharmacotherapeutic and psychotherapeutic interventions designed to improve stress resilience in substance-dependent individuals. The candidate would also use the time and funding provided through this award to continue to expand her activities in mentoring fellows and junior faculty.